The Aldosterone Synthase Inhibitor FAD286 is Suitable for Lowering Aldosterone Levels in ZDF Rats but not in db/db Mice

Abstract

Inhibition of aldosterone synthase is an alternative treatment option to mineralocorticoid receptor antagonism to prevent harmful aldosterone actions. FAD286 is one of the best characterized aldosterone synthase inhibitors to date. FAD286 improves glucose tolerance and increases glucose-stimulated insulin secretion in obese and diabetic ZDF rats. However, there is limited knowledge about the dose-dependent effects of FAD286 on plasma aldosterone, corticosterone, and 11-deoxycorticosterone in ZDF rats and in db/db mice, a second important rodent model of obesity and type 2 diabetes. In addition, effects of FAD286 on plasma steroids in mice and rats are controversial. Therefore, obese Zucker diabetic fatty (ZDF) rats and db/db mice were treated with FAD286 for up to 15 weeks and plasma steroids were evaluated using highly sensitive liquid chromatography-tandem mass spectrometry. In ZDF rats, FAD286 (10 mg/kg/d) treatment resulted in nearly complete disappearance of plasma aldosterone while corticosterone levels remained unaffected and those of 11-deoxycorticosterone were increased ~4-fold compared to vehicle control. A lower dose of FAD286 (3 mg/kg^/d) showed no effect on plasma aldosterone or corticosterone, but 11-deoxycorticosterone was again increased ~4-fold compared to control. In contrast to ZDF rats, a high dose of FAD286 (40 mg/kg/d) did not affect plasma aldosterone levels in db/db mice although 11-deoxycorticosterone increased ~2.5-fold. A low dose of FAD286 (10 mg/kg/d) increased plasma aldosterone without affecting corticosterone or 11-deoxycorticosterone. In conclusion, the aldosterone synthase inhibitor, FAD286, lowers plasma aldosterone in obese ZDF rats, but not in obese db/db mice.

Key words

aldosterone synthase inhibition - steroid hormones - db/db mice - ZDF rats

• References

• 1 Azizi M, Amar L, Menard J. Aldosterone synthase inhibition in humans. Nephrol Dial Transplant 2013; 28: 36-43
• 2 Rossier BC, Baker ME, Studer RA. Epithelial sodium transport and its control by aldosterone: the story of our internal environment revisited. Physiol Rev 2015; 95: 297-340
• 3 Tuck ML, Sowers J, Dornfeld L, Kledzik G, Maxwell M. The effect of weight reduction on blood pressure, plasma renin activity, and plasma aldosterone levels in obese patients. N Engl J Med 1981; 304: 930-933
• 4 Garg R, Adler GK. Aldosterone and the mineralocorticoid receptor: Risk factors for cardiometabolic disorders. Curr Hypertens Rep 2015; 17: 52
• 5 Hofmann A, Peitzsch M, Brunssen C, Mittag J, Jannasch A, Frenzel A, Brown NF, Weldon SM, Eisenhofer G, Bornstein SR, Morawietz H. Elevated steroid hormone production in the db/db mouse model of obesity and type 2 diabetes. Horm Metab Res 2017; 49: 43-49
• 6 Deinum J, Riksen NP, Lenders JW. Pharmacological treatment of aldosterone excess. Pharmacol Ther 2015; 154: 120-133
• 7 Rigel DF, Fu F, Beil M, Hu CW, Liang G, Jeng AY. Pharmacodynamic and pharmacokinetic characterization of the aldosterone synthase inhibitor FAD286 in two rodent models of hyperaldosteronism: comparison with the 11beta-hydroxylase inhibitor metyrapone. J Pharmacol Exp Ther 2010; 334: 232-243
• 8 Menard J, Rigel DF, Watson C, Jeng AY, Fu F, Beil M, Liu J, Chen W, Hu CW, Leung-Chu J, LaSala D, Liang G, Rebello S, Zhang Y, Dole WP. Aldosterone synthase inhibition: cardiorenal protection in animal disease models and translation of hormonal effects to human subjects. J Transl Med 2014; 12: 340
• 9 Fiebeler A, Nussberger J, Shagdarsuren E, Rong S, Hilfenhaus G, Al-Saadi N, Dechend R, Wellner M, Meiners S, Maser-Gluth C, Jeng AY, Webb RL, Luft FC, Muller DN. Aldosterone synthase inhibitor ameliorates angiotensin II-induced organ damage. Circulation 2005; 111: 3087-3094
• 10 Lea WB, Kwak ES, Luther JM, Fowler SM, Wang Z, Ma J, Fogo AB, Brown NJ. Aldosterone antagonism or synthase inhibition reduces end-organ damage induced by treatment with angiotensin and high salt. Kidney Int 2009; 75: 936-944
• 11 Amar L, Azizi M, Menard J, Peyrard S, Watson C, Plouin PF. Aldosterone synthase inhibition with LCI699: a proof-of-concept study in patients with primary aldosteronism. Hypertension 2010; 56: 831-838
• 12 Menard J, Gonzalez MF, Guyene TT, Bissery A. Investigation of aldosterone-synthase inhibition in rats. J Hypertens 2006; 24: 1147-1155
• 13 Mulder P, Mellin V, Favre J, Vercauteren M, Remy-Jouet I, Monteil C, Richard V, Renet S, Henry JP, Jeng AY, Webb RL, Thuillez C. Aldosterone synthase inhibition improves cardiovascular function and structure in rats with heart failure: a comparison with spironolactone. Eur Heart J 2008; 29: 2171-2179
• 14 Gamliel-Lazarovich A, Gantman A, Coleman R, Jeng AY, Kaplan M, Keidar S. FAD286, an aldosterone synthase inhibitor, reduced atherosclerosis and inflammation in apolipoprotein E-deficient mice. J Hypertens 2010; 28: 1900-1907
• 15 Ray JA, Kushnir MM, Palmer J, Sadjadi S, Rockwood AL, Meikle AW. Enhancement of specificity of aldosterone measurement in human serum and plasma using 2D-LC-MS/MS and comparison with commercial immunoassays. J Chromatogr B Analyt Technol Biomed Life Sci 2014; 970: 102-107
• 16 Peitzsch M, Dekkers T, Haase M, Sweep FC, Quack I, Antoch G, Siegert G, Lenders JW, Deinum J, Willenberg HS, Eisenhofer G. An LC-MS/MS method for steroid profiling during adrenal venous sampling for investigation of primary aldosteronism. J Steroid Biochem Mol Biol 2015; 145: 75-84
• 17 Hansen M, Jacobsen NW, Nielsen FK, Bjorklund E, Styrishave B, Halling-Sorensen B. Determination of steroid hormones in blood by GC-MS/MS. Anal Bioanal Chem 2011; 400: 3409-3417
• 18 Siragy HM, Xue C. Local renal aldosterone production induces inflammation and matrix formation in kidneys of diabetic rats. Exp Physiol 2008; 93: 817-824
• 19 Hofmann A, Brunssen C, Peitzsch M, Martin M, Mittag J, Jannasch A, Engelmann F, Brown NF, Weldon SM, Huber J, Streicher R, Deussen A, Eisenhofer G, Bornstein SR, Morawietz H. Aldosterone synthase inhibition improves glucose tolerance in zucker diabetic fatty (ZDF) Rats. Endocrinology 2016; 157: 3844-3855
• 20 King AJ. The use of animal models in diabetes research. Br J Pharmacol 2012; 166: 877-894
• 21 Fredersdorf S, Endemann DH, Luchner A, Heitzmann D, Ulucan C, Birner C, Schmid P, Stoelcker B, Resch M, Muders F, Riegger GA, Weil J. Increased aldosterone levels in a model of type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes 2009; 117: 15-20
• 22 Briones AM, Nguyen Dinh Cat A, Callera GE, Yogi A, Burger D, He Y, Correa JW, Gagnon AM, Gomez-Sanchez CE, Gomez-Sanchez EP, Sorisky A, Ooi TC, Ruzicka M, Burns KD, Touyz RM. Adipocytes produce aldosterone through calcineurin-dependent signaling pathways: implications in diabetes mellitus-associated obesity and vascular dysfunction. Hypertension 2012; 59: 1069-1078
• 23 Weldon SM, Cerny MA, Gueneva-Boucheva K, Cogan D, Guo X, Moss N, Parmentier JH, Richman JR, Reinhart GA, Brown NF. Selectivity of BI 689648, a novel, highly selective aldosterone synthase inhibitor: comparison with FAD286 and LCI699 in nonhuman primates. J Pharmacol Exp Ther 2016; 359: 142-150
• 24 Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 2001; 29: e45
• 25 Langbein H, Brunssen C, Hofmann A, Cimalla P, Brux M, Bornstein SR, Deussen A, Koch E, Morawietz H. NADPH oxidase 4 protects against development of endothelial dysfunction and atherosclerosis in LDL receptor deficient mice. Eur Heart J 2016; 37: 1753-1761
• 26 Engeli S, Bohnke J, Gorzelniak K, Janke J, Schling P, Bader M, Luft FC, Sharma AM. Weight loss and the renin-angiotensin-aldosterone system. Hypertension 2005; 45: 356-362
• 27 Goodfriend TL, Kelley DE, Goodpaster BH, Winters SJ. Visceral obesity and insulin resistance are associated with plasma aldosterone levels in women. Obes Res 1999; 7: 355-362
• 28 Strushkevich N, Gilep AA, Shen L, Arrowsmith CH, Edwards AM, Usanov SA, Park HW. Structural insights into aldosterone synthase substrate specificity and targeted inhibition. Mol Endocrinol 2013; 27: 315-324
• 29 Holst JP, Soldin OP, Guo T, Soldin SJ. Steroid hormones: relevance and measurement in the clinical laboratory. Clin Lab Med 2004; 24: 105-118